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Creator

Dezfuli, Ghazaul

Advisor

Gillis, Richard

Abstract

Melanocortin neural circuits are important regulators of food intake (FI) and body weight (BW). The hypothesis of the first part of my dissertation is that the dorsal motor nucleus of the vagus (DMV) represents an important output nucleus of central melanocortin signalling. This hypothesis was tested by examining the role of the DMV in the prevention and treatment of obesity caused by a knockout of the melanocortin 4-receptor (Mc4R). The role of the DMV was tested by performing a bilateral subdiaphragmatic vagotomy (SDV) which results in cell loss in the DMV.

In the first study, Mc4R -/- mice were used that had not reached full obesity, while in study 2, Mc4R -/- mice were used that were severely obese. In both studies, complete SDV blunted the obesity associated with this genotype. The anti-obesity effect of SDV was not associated with a decrease in FI. Complete SDV reduced visceral mesenteric white adipose tissue in both studies. Additionally, Mc4R -/- mice after SDV had increased energy expenditure during the dark cycle and a decreased light cycle respiratory exchange ratio indicating an increase in the utilization of lipids as an energy source.

The second part of my dissertation focused on determining the effectiveness and mechanisms whereby nicotine and drugs that interact with nicotinic receptors (nAChRs) can influence BW in mice. The hypotheses from the second part of my dissertation are that nicotine's effect on BW is mediated through the melanocortin system at the α4β2 nAChR, and involves inhibition of hypothalamic adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). To test these hypotheses, I used Mc4R -/- mice, drugs selective for the α4β2 nAChR, and measured AMPK activity. I found that (1) nicotine causes weight loss independent of the brain melanocortin system; (2) nicotine's effect to decrease BW is in part due to interaction with the α4β2 nAChR; (3) nicotine's interaction with the nAChR involves desensitization as opposed to activation; and (4) nicotine reduces BW independent of hypothalamic AMPK inhibition. In summary, my studies revealed that both SDV and nicotine have a robust effect to reduce BW.